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Publication numberUS3470182 A
Publication typeGrant
Publication dateSep 30, 1969
Filing dateFeb 9, 1967
Priority dateFeb 9, 1967
Publication numberUS 3470182 A, US 3470182A, US-A-3470182, US3470182 A, US3470182A
InventorsGoetz E Hardtmann, Hans Ott
Original AssigneeSandoz Ag
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
4-amino-substituted quinazolines
US 3470182 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent 3,470,182 4-AMINO-SUBSTITUTED QUINAZOLINES Goetz E. Hardtmann, Florham Park, and Hans Ott, Convent Station, N.J., assignors to Sandoz Inc., Hanover,

N6 Drawing. Filed Feb. 9, 1967, Ser. No. 614,813 1m. 01. 007.1 51/48, 51/72,- A61k 27/00 US. Cl. 260256.4 Claims ABSTRACT OF THE DISCLOSURE There are disclosed various 4-amino-substituted quinazolines, which are central nervous system stimulants and may be used as antidepressants.

I l 1 wherein R represents 4-lower alkylpiperazino, the lower alkyl substituent preferably containing from 1 to 4 carbon atoms, e.g., 4-methylpiperazino and 4-ethylpiperazino; 4-(5 hydroxyethyl)piperazino; 4 phenylpipera- Zino; 1 lower alkyl-4-piperidylamino, the lower alkyl substituent preferably containing from 1 to 4 carbon atoms, e.g., 1-methyl-4-piperidylamino and 1-ethyl-4-piperidylamino; hexamethylenimino; heptamethylenimino; w-(Z pyridyl)lower alkylamino, the lower alkyl substituentpreferably containing from 1 to 4 carbon atoms, e.g., B-(2-pyridyl) ethylamino and 'y-(2-pyridy1)propyla mino; w-(3-indolyl)lower alkylamino, the lower alkyl substituent preferably containing from 1 to 4 carbon atoms, e.g., fl-(3-indolyl)ethylan1ino and y-(B-indolyl) propylamino; l-indanylamino or Z-indanylamino.

The above compounds are prepared by reacting a 4- haloquinazoline, the halo substituent preferably being chloro or bromo, with an appropriate amine of the formula RH, wherein R is as defined above, as illustrated by the following reaction scheme:

a l t wherein R is as previously defined and X represents halo, preferably chloro or bromo.

The reaction may be carried out at room temperature (20-25 C.) or at elevated temperatures up to reflux temperature. The particular temperature employed will for the most part be dependent upon the reactivity of the amine. The reaction can be carried out in the presence of an inert organic solvent, e.g., methylene chloride, benzene, toluene and xylene. However, the use of a solvent is not necessary since an excess of the amine can be employed for this purpose. When a solvent is employed it is preferred to carry out the reaction in the presence of a tertiary amine, e.g., triethylamine and the like, to take up the hydrogen halide liberated during the reaction. When the reaction is carried out employing an excess of the amine reactant in lieu of a solvent a suflicient excess thereof is employed to also take up the liberated hydro- Patented Sept. 30, 1969 'fee gen halide. The resulting products are readily recovered employing conventional techniques.

The reactants employed in the above process are either known and can be prepared as described in the literature or canbe prepared from available materials in analogous manner.

The compounds of structural Formula I are useful because they possess pharmacological activity in animals. In particular, the compounds are central nervous system stimulants and can be used as antidepressants. For such usage the compounds can be admixed with conventional pharmaceutical carriers or diluents and administered internally in the form of tablets, capsules, elixirs, solutions, emulsions or suspensions. The compounds may also be administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriately suitable acid and accordingly are included within the scope of this invention. Representative of such salts are the hydrochloride, hydrobromide, sulfate, phosphate, oxalate, citrate, tartrate, methane sulfonate and p-toluenesulfonate. The dosage administered will, of course vary depending upon the compound employed and mode of administration (oral or parenteral). However, in general, satisfactory results are obtained when administered at a daily dosage of from about 10 milligrams to about 30 milligrams per kilogram of body Weight preferably given in divided doses 2 to 4 times a day or in sustained release form. For larger mammals as well as the smaller domestic mammals, dosage forms suitable for internal administration comprise from about 25 milligrams to about 300 milligrams of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.

A representative formulation for oral administration is a tablet (prepared by standard tableting techniques) and containing the following ingredients.

Ingredient: Parts by wt. 4- (4-1nethylpiperazino) quinazoline 5O Tragacanth 2 Lactose 39.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5

The following examples show representative compounds encompassed within the scope of this invention and the manner in which such compounds are prepared. However, it is to be understood that the examples are for purposes of illustration only and are not intended as in any way limiting the scope of the invention which is defined in the appended claims.

EXAMPLE 1 4- (4-methylpiperazino) quinazoline EXAMPLE 2 4- [4- fi hydroxyethyl) pi perazino] quinazoline To a solution of 12 g. of 4chloroquinazoline in 200 ml. of methylene chloride is added 11.4 g. of 4-(fi-hydroxyethyl)piperazine and 17.8 g. of triethylamine. The resulting mixture is stirred at room temperature for 1 hour, then washed twice with 50 ml. (each) of water and then dried over anhydrous sodium sulfate and evaporated in vacuo to obtain 4-[4-(fi-hydroxyethyl)piperazino] quinazoline as an oil.

The dihydrochloride salt thereof, M.P. 241243 C., is obtained by treating a cooled (ice bath) solution of the oil in 150 ml. of methylene chloride with hydrogen chloride gas, precipitating the salt by the addition of diethyl ether, recovering the salt by filtration and recrystallization the same from methylene chloride.

EXAMPLE 3 4- (4-phenylpiperazino) quinazoline To a solution of 12 g. of 4-chloroquinazoline in 50 ml. of chloroform is added 17.4 g. of triethylamine and 14.2 g. of 4-phenylpiperazine. The resulting mixture is stirred at room temperature for 1 hour, then washed twice with 50 ml. (each) of water and then dried over anhydrous sodium sulfate and evaporated in vacuo to obtain 4-(4-phenylpiperazino)quinazoline as an oil.

The hydrochloride salt thereof, M.P. 225230 C., is obtained by treating a cooled (ice bath) solution of the oil in 150 ml. of chloroform with hydrogen chloride gas, precipitating the salt by the addition of diethyl ether, recovering the salt by filtration and recrystallizing the same from methylene chloride.

4 EXAMPLE 4 4- 1-methyl-4-piperidylamino) quinazoline A solution of 8 g. of 4-chloroquinazoline and 18 g. of l-methyl-4-aminopiperidine in 150 ml. of benzene is stirred for 15 hours at room temperature and then evaporated in vacuo. The residue is dissolved in chloroform and the resulting solution extracted twice with 50 ml. (each) of water and then evaporated in vacuo. The residue is crystallized from benzene to obtain 4-(1-methyl-4-piperidylamino)quinazoline, M.P. 179-181 C.

The dihydrochloride salt thereof, M.P. 297-300 C., is prepared by treating the base with hydrogen chloride gas in conventional manner.

EXAMPLE 5 4-[ [18- (2-pyridyl) ethyl] amino] quinazoline To a solution of 11 g. of 4-chloroquinazoline in ml. of benzeneis added 19 g. of Z-(fl-aminoethyhpyridine. The resulting mixture is stirred for 2 hours at room temperature and then evaporated in vacuo. The residue is dissolved in chloroform and the resulting solution washed once with 150 ml. of 10% aqueous sodium bicarbonate solution, then three times with ml. (each) of water and then evaporated in vacuo to obtain 4-[[fi-(2-pyridyl) ethylJamino] quinazoline, M.P. 204-207" C.

EXAMPLE 6 4-(2-indanylamino)quinazoline EXAMPLE 7 4-[ p- 3-indolyl) ethyl] amino] quinazoline I CH CH and the pharmaceutically acceptable acid addition salts thereof, wherein R represents 4-lower alkylpiperazino, 4 phenylpiperazino, 4-(fl-hydroxyethyl)piperazino, l-lower alkyl-4-piperidylamino, hexamethylenimino, heptamethylenimino, w-(2-pyridyl)lower alkylamino, w-(3-indoly1) lower alkylamino, l-indanylamino or Z-indanylamino.

2. The compound of claim 1 which is 4-(4-methylpiperazino quinazoline.

3. The compound of claim 1 which is 4-(1-methyl-4- piperidylamino quinazoline.

4. The compound of claim 1 which is 4-[ [,B-(Z-pyridyl) ethyl] amino] quinazoline.

5. The compound of claim 1 which is 4-[ [B-(3-indoly1) ethyl] amino] quinazoline.

6. The compound of claim 1 which is 4-(2-indanylamino) quinazoline.

7. The compound of claim 1 which is 4-[4-(,8-hydroxyethyl) piperazino] quinazoline.

8. The compound of claim 1 which is 4-(4-phenylpiperazino quinazoline.

References Cited UNITED STATES PATENTS 5/1965 Scarborough et a1. 260256.4 1/ 1967 Blatter 260-256.4

U.S. C1. X.R.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3184462 *Mar 10, 1961May 18, 1965Mead Johnson & CoCertain 4-substituted quinazolines
US3301855 *Mar 2, 1964Jan 31, 1967Ciba Geigy CorpDerivatives of 4-nu-(2-nu, nu-dimethylaminolower alkyl)-amino quinazoline
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3853891 *Jun 20, 1973Dec 10, 1974Sandoz AgN-(n-(cyanoalkyl)-n-nitroso)amino-aminoalcohol
US4091098 *Apr 25, 1977May 23, 1978Merck & Co., Inc.3-(1-PIPERAZINYL)-1,2,4-BENZOTRIAZINES AND N-oxides
US5145843 *Apr 7, 1989Sep 8, 1992DowelancoFor plants
US5296484 *Mar 20, 1989Mar 22, 1994DowelancoQuinoline derivatives
US5571815 *Mar 11, 1993Nov 5, 1996Hoechst AktiengesellschaftSubstituted pyrimidines, process for their preparation, and their use as pesticides and fungicides
US5580870 *Dec 10, 1993Dec 3, 1996Zeneca LimitedQuinazoline derivatives
US5614627 *Sep 12, 1994Mar 25, 1997Eisai Co., Ltd.Quinazoline compounds
US5658902 *Dec 22, 1994Aug 19, 1997Warner-Lambert CompanyQuinazolines as inhibitors of endothelin converting enzyme
US5773444 *Apr 14, 1997Jun 30, 1998Warner-Lambert CompanyQuinazolines as inhibitors of endothelin converting enzyme
US6265398Oct 23, 1998Jul 24, 2001Hoechst Schering Agrevo GmbhSubstituted pyridines/pyrimidines, their preparation and their use as pesticides
US6596727Mar 15, 1996Jul 22, 2003Hoechst AktiengesellschaftSubstituted pyrimidines, processes for their preparation, and their use as pesticides and fungicides
US6734180Mar 22, 2000May 11, 2004Daiichi Suntory Pharma Co., Ltd.NF-κB inhibitor comprising an indan derivative as an active ingredient
US8246966Feb 6, 2009Aug 21, 2012University Of Georgia Research Foundation, Inc.Trypanosome microsome system and uses thereof
US8268843Aug 31, 2009Sep 18, 2012Dow Agrosciences, Llc.5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines and their use as agrochemicals
US8338433Nov 21, 2007Dec 25, 2012University Of Georgia Research Foundation, Inc.Tyrosine kinase inhibitors as anti-kinetoplastid agents
EP0194161A2 *Mar 7, 1986Sep 10, 1986Sankyo Company LimitedCyclopenta[d]pyrimidine derivatives, their preparation and use
EP0326329A2 *Jan 25, 1989Aug 2, 1989DowElancoQuinazoline derivatives
EP0602851A1Dec 3, 1993Jun 22, 1994Zeneca LimitedQuinazoline derivatives
EP0669324A1 *Sep 12, 1994Aug 30, 1995Eisai Co., Ltd.Quinazoline compound
EP1488792A2 *Dec 8, 1994Dec 22, 2004Aventis Pharmaceuticals Products Inc.Quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
EP2014662A1 *Jul 12, 2007Jan 14, 2009Bayer Schering Pharma AktiengesellschaftIndolyl alkyl thieno-pyrimidyl amines as modulators of EP2 receptors
WO1993019050A1 *Mar 10, 1993Sep 30, 1993Hoechst AgSubstituted pyrimidines and their use as pesticides
WO1995015758A1 *Dec 8, 1994Jun 15, 1995Hsu Chin Yi JennyAryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase
WO1996019474A1 *Nov 27, 1995Jun 27, 1996Warner Lambert CoQuinazolines as inhibitors of endothelin converting enzyme
WO1997038979A1 *Apr 1, 1997Oct 23, 1997Hoechst Schering Agrevo GmbhSubstituted pyridines/pyrimidines, process for their production and their use as pest control agents
WO2000005234A1 *Jul 22, 1999Feb 3, 2000Keiichi AbeNF-λB INHIBITORS CONTAINING INDAN DERIVATIVES AS THE ACTIVE INGREDIENT
WO2009007421A1 *Jul 10, 2008Jan 15, 2009Bayer Schering Pharma AgIndolylalkylthienopyrimidylamines as modulators of the ep2 receptor
WO2010025451A2 *Aug 31, 2009Mar 4, 2010Dow Agrosciences Llc5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines and their use as agrochemicals
Classifications
U.S. Classification544/284, 544/293
International ClassificationC07D403/12, C07D239/94, C07D401/12
Cooperative ClassificationC07D401/12, C07D239/94, C07D403/12
European ClassificationC07D239/94, C07D401/12, C07D403/12